DNase I hypersensitivity analysis of the mouse brain and retina identifies region-specific regulatory elements

Epigenetics & Chromatin

Thomas A Reh²  John Stamatoyannopoulos⁴  Michael A Bender³  R Scott Hansen⁴  Theresa K Canfield⁴  Jeff Vierstra⁴  Richard S Sandstrom⁴  Peter Sabo⁴  Robert Thurman⁴  Kyle Siebenthall⁴  Anna La Torre²  Joseph A Brzezinski⁵  Matthew S Wilken¹ 

[1] Molecular and Cellular Biology Program, University of Washington, MCB Program Office, T-466 Health Sciences Building, Box 357275, Seattle, WA 98195, USA;Department of Biological Structure, University of Washington, 1959 NE Pacific Street, Box 357420, Seattle, WA 98195, USA;Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA;Department of Genome Sciences, University of Washington, Foege Building S-250, 3720 15th Ave NE, Box 355065, Seattle, WA 98195, USA;Current address: Department of Ophthalmology, University of Colorado School of Medicine, 1675 Aurora Court, Aurora, CO 80045, USA

关键词: Cis-regulation;    DNase-seq;    Retina;    Central nervous system;   

Others  :  1143291
DOI  :  10.1186/1756-8935-8-8

 received in 2014-12-29, accepted in 2015-01-27,  发布年份 2015

【 摘 要 】

Background

The brain, spinal cord, and neural retina comprise the central nervous system (CNS) of vertebrates. Understanding the regulatory mechanisms that underlie the enormous cell-type diversity of the CNS is a significant challenge. Whole-genome mapping of DNase I-hypersensitive sites (DHSs) has been used to identify cis-regulatory elements in many tissues. We have applied this approach to the mouse CNS, including developing and mature neural retina, whole brain, and two well-characterized brain regions, the cerebellum and the cerebral cortex.

Results

For the various regions and developmental stages of the CNS that we analyzed, there were approximately the same number of DHSs; however, there were many DHSs unique to each CNS region and developmental stage. Many of the DHSs are likely to mark enhancers that are specific to the specific CNS region and developmental stage. We validated the DNase I mapping approach for identification of CNS enhancers using the existing VISTA Browser database and with in vivo and in vitro electroporation of the retina. Analysis of transcription factor consensus sites within the DHSs shows distinct region-specific profiles of transcriptional regulators particular to each region. Clustering developmentally dynamic DHSs in the retina revealed enrichment of developmental stage-specific transcriptional regulators. Additionally, we found reporter gene activity in the retina driven from several previously uncharacterized regulatory elements surrounding the neurodevelopmental gene Otx2. Identification of DHSs shared between mouse and human showed region-specific differences in the evolution of cis-regulatory elements.

Conclusions

Overall, our results demonstrate the potential of genome-wide DNase I mapping to cis-regulatory questions regarding the regional diversity within the CNS. These data represent an extensive catalogue of potential cis-regulatory elements within the CNS that display region and temporal specificity, as well as a set of DHSs common to CNS tissues. Further examination of evolutionary conservation of DHSs between CNS regions and different species may reveal important cis-regulatory elements in the evolution of the mammalian CNS.

【 授权许可】

   
2015 Wilken et al.; licensee BioMed Central.

【 图 表 】

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